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F. Hirai



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    MO03 - Thymic Malignancies (ID 123)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO03.10 - A multicenter prospective study of carboplatin and paclitaxel for advanced thymic carcinoma: West Japan Oncology Group 4207L (ID 987)

      10:30 - 12:00  |  Author(s): F. Hirai

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC.

      Methods
      Pts with Masaoka’s stage III to IVb TC, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Based on the SWOG 2-stage design, the planned sample size of 40 pts was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.

      Results
      From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36–84); 23/16 males/females; 3/10/26 with Masaoka’s stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval [CI], 21-53%; P = 0.031). The median PFS was 7.5 mo (6.2-12.3 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (95% CI, 69-93%) and 71% (95% CI, 54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death.

      Conclusion
      CbP showed high efficacy in advanced TC. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-007 - Phase I study of the ALK inhibitor LDK378 in Japanese patients with advanced, ALK-rearranged NSCLC and other tumors harboring genetic ALK alterations (ID 736)

      09:30 - 16:30  |  Author(s): F. Hirai

      • Abstract

      Background
      Genetic alterations in anaplastic lymphoma kinase (ALK), including ALK rearrangements, occur in 3–7% of NSCLC. ALK-rearranged (ALK+) NSCLC is sensitive to the tyrosine kinase inhibitor (TKI) crizotinib, but acquired resistance inevitably develops. LDK378 is a novel, potent ALK TKI, with significant preclinical antitumor activity, even in crizotinib-resistant models. An ongoing pivotal Phase I study in Western patients established the MTD as 750 mg/day, with overall response rates (ORRs) of 58% in all patients (n=114) and 57% in crizotinib-resistant patients (n=79), treated at ≥400 mg/day (Shaw, et al. ASCO 2013, Abstr 8010). The primary objective of the present study was to estimate the MTD and/or recommended dose in Japanese patients with tumors harboring ALK alterations; secondary objectives included safety, PK, and preliminary antitumor activity.

      Methods
      In this multicenter, open-label, dose-escalation study, patients with ALK alterations were enrolled. Japanese patients (ECOG PS 0–2) with locally advanced or metastatic disease that had progressed on standard therapy, or for which no standard therapy exists, were eligible. LDK378 was administered orally at doses of 300–750 mg once daily (21-day cycles, with a PK run-in period). Adaptive dose escalations were guided by a Bayesian logistic regression model with overdose control. Patients were treated until disease progression, unacceptable toxicity, or consent withdrawal.

      Results
      As of April 29, 2013, the dose-escalation part had enrolled 19 patients (median age 45 years; 11 female), including 18 patients with ALK+ NSCLC (by FISH assay) and one patient with inflammatory myofibroblastic tumor (IMT) harboring an ALK alteration. Fourteen patients with NSCLC had received prior ALK inhibitors (crizotinib, n=9; others [ASP3026 and CH5424802], n=5) and 4 patients with NSCLC were ALK inhibitor-naïve. Patients were treated at 300 mg (n=3), 450 mg (n=6), 600 mg (n=4), and 750 mg (n=6). Two DLTs occurred, at 600 mg (Grade 3 lipase increase) and 750 mg (Grade 3 drug-induced liver injury); the MTD was 750 mg. The most common AEs regardless of drug relationship were nausea (n=18, 95%), diarrhea (n=14, 74%), vomiting (n=14, 74%), blood creatinine increase (n=12, 63%), decreased appetite (n=10, 53%), and fatigue (n=7, 37%). The most common Grade 3/4 AEs were hepatic enzyme increase (n=3) and drug-induced liver injury/abnormal hepatic function (n=2). Among 18 patients with NSCLC (all doses), the ORR (confirmed responses) was 50% (95%CI 26.0─74.0; partial responses [PRs], n=9). PRs were observed in 7/9 crizotinib-pretreated patients (2 unconfirmed). In patients pretreated with other ALK inhibitors, 3/5 had a PR (including 1 who also received crizotinib, and 2/4 who received CH5424802). The patient with IMT also achieved a PR. The preliminary PK profile was similar to that seen in Western patients.

      Conclusion
      The MTD was 750 mg once daily in Japanese patients. The safety profile was tolerable and comparable to that of Western patients; gastrointestinal toxicities were most common, and the most frequent Grade ≥3 AEs were liver toxicities. LDK378 exhibited antitumor activity against ALK+ NSCLC, in both crizotinib-resistant and other ALK inhibitor-resistant patients. An expansion part will further evaluate oral LDK378 750 mg. ClinicalTrials.gov identifier NCT01634763.

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    P2.07 - Poster Session 2 - Surgery (ID 190)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P2.07-008 - Radiological-pathological correlation for resected small lung nodules with pure ground glass opacity detected by high-resolution computed tomography (ID 989)

      09:30 - 16:30  |  Author(s): F. Hirai

      • Abstract

      Background
      The term "ground glass opacity (GGO)" on high-resolution computed tomography (HRCT) is defined as “hazy increased attenuation in the lung that does not obliterate the bronchial and vascular margins” by Fleischner Society. The identification of small lung nodules of GGO on HRCT often implies lung cancer, especially well differentiated adenocarcinoma or atypical adenomatous hyperplasia; however, there is no objective definition of GGO, such as the computed tomography number.

      Methods
      A single institutional retrospective study. To access the correlation between radiological and pathological diagnosis of the patients with small pure GGO on HRCT. Thirty-nine consecutive surgically resected patients with pure GGO less than 30 mm detected by HRCT between July 2008 and March 2013 in our department were retrospectively examined. The median follow-up of these patients was 28.7 (1.9 - 92.7) months.

      Results
      The median age of the patients was 64 (range 42-82) years old, 19 patients were male and 20 were female. The median size of major axis of lung nodules was 11 (range 5-25) mm, and 29 (74.4%) were less than 15 mm and 10 were between 15 and 30 mm in diameter. Twenty-eight (71.8%) patients had a single nodule, whereas 11 patients had multiple nodules. Six of the 39 patients had a previous history of malignancy (three lung cancers and three other cancers). During the follow-up period, 22 patients had nodules that were stable in size or appearance, and five patients had nodules that either became enlarged or in which the opacity increased, as determined by HRCT. The other twelve patients were operated based on the findings of their first HRCT, basically by the attending surgeons’ decision. Partial resection was performed in seven patients, segmentectomy in 11 patients and lobectomy was performed in 21 patients. Histologically, thirty-seven patients had adenocarcinoma, one had small cell carcinoma and one had a benign tumor. Among the 37 patients with adenocarcinoma, 14 were adenocarcinoma in situ, five tumors were minimally invasive and 18 were invasive according to the IASLC/ATS/ERS classification. There was no postoperative recurrence during the follow-up period.

      Conclusion
      Even if the small pulmonary nodules present as pure GGO, they may still be adenocarcinoma with an invasive nature. The timing of surgery should be considered carefully so that a chance to achieve a cure of such patients is not missed.